Abstract

Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

Recurring mutations in ETP-ALL. The figures show mutations for the 12 WGS cases, and the recurrence cohort of 94 cases sequenced by Sanger sequencing. The majority of cases had matched remission DNA to distinguish somatic from inherited variants. Where remission DNA was not available, but variants are known or predicted to be deleterious, mutations are shown as ‘variants’. The results of recurrence screening for additional genes sequenced are shown in and ). The schematics are based on the following NCBI protein reference sequences: GATA3 NP_001002295, DNM2 NP_001005360, ECT2L NP_001071174, EZH2 NP_001190176, PHF6 NP_001015877.1 and RUNX1 NP_001745.

a, Data are shown for 106 T-ALL cases, including the 12 cases that were subjected to whole-genome sequencing (arrowed), and 94 recurrence cases (52 ETP ALL and 42 non-ETP T-ALL). Cases have been grouped by ETP status, and cases lacking any mutations are shown to the left, followed by cases with NRAS and FLT3 mutations. Genes identified as novel targets of mutation in T-ALL are labelled green. Four cases died while in remission and are excluded from outcome analysis. b, Frequency of somatic alterations targeting haematopoietic and lymphoid development in ETP and non-ETP T-ALL, showing an increased frequency of lesions in these pathways in ETP ALL. ***P < 0.0001.